Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1997-07-11
2003-09-30
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S135100, C424S144100, C424S145100, C424S153100, C424S154100, C424S158100, C514S002600
Reexamination Certificate
active
06627195
ABSTRACT:
The present invention relates to particular binding agents which can be used in the treatment of inflammatory, autoimmune or allergic diseases.
CD23 (FC&egr;RII) is a type II molecule of the C-lectin family which also includes the lymphocyte homing receptor (MEL-14) and the endothelial leukocyte adhesion molecule-1 (ELAM 1). It is a low affinity receptor for IgE. In humans a variety of haematopoietic cell types express CD23 on their surface, including follicular dendritic cells, B cells, T cells and macrophages. CD23 molecules are also found in soluble forms in biological fluids. Soluble CD23 (sCD23) molecules are formed by proteolytic cleavage of transmembrane receptors. CD23 has pleiotropic activities including mediation of cell adhesion, regulation of IgE and histamine release, rescue of B cells from apoptosis and regulation of myeloid cell growth. These functional activities are mediated through the binding to specific ligands of cell-associated CD23, or sCD23, the latter acting in a cytokine-like manner (Conrad, D. H.,
Annu Rev Immunol
8, 623-645 1990); Delespesse, G., et al.,
Adv Immunol
49, 149-191 (1991); Bonnefoy, J. Y., et al.,
Curr Opin Immunol
5,944-947 (1993)).
Increased expression of CD23 has been observed in a number of inflammatory diseases. CD23 has been identified in synovial biopsies from patients with chronic synovitis, and sCD23 can be measured at concentrations exceeding the normal range in the serum and synovial fluid of patients with rheumatoid arthritis (Bansal, A. S., Oliver, W., Marsh, M. N., Pumphrey, R. S., and Wilson, P. B.,
Immunology
79, 285289 (1993); Hellen, E. A., Rowlands, D. C., Hansel, T. T., Kitas, G. D., and Crocker, J. J.,
Clin Pathol
44, 293-296 (1991); Chomarat, P., Brioloay, J., Banchereau, J., & Miossec, P.,
Arthritis Rheum
86, 234-242 (1993); Bansal, A., et al,
Clin Exp Immunol
89, 452-455 (1992); Rezonzew, R., & Newkirk, M. M.,
Clin Immunol Immunopathol
71, 156-163 (1994)). In addition, levels of serum sCD23 in rheumatoid arthritis patients are related to disease status and correlate with serum rheumatoid factor (Bansal, A. S., et al.,
Clin Exp Rheumatol
12, 281-285 (1994)). Pro-inflammatory cytokines appear to be particularly important in rheumatoid arthritis, and a central role for TNF-&agr; and IL-1&bgr; in the destruction of arthritic joints has been postulated (Brennan, F. M., Chantry, D., Jackson, A., Maini, R., & Feldman, M.,
Lancet
2, 244-247 (1989); Brennan, F. M., Maini, R. M., & Feldman M.,
Br J Rheumatol
31, 293-298 (1992)).
It has also been postulated that CD23-CD21 interactions may play a role in the control of IgE production (Flores-Romo L. et al.,
Science
261 1038-1041 (1993); Aubry et al.,
Nature
358, 505-507 (1992)).
CD11b and CD11c are adhesion molecules Fat participate in many cell-cell and cell-matrix interactions. CD11b/CD18 and CD11/CD18 (an association of CD11b and CD18 and of CD11c and CD18 respectively) have been reported to bind several ligands, including CD54, fibrinogen, factor X, LPS, Con A and zymosan (Springer, T. A.,
Nature
346, 425-434(1990)). The role of these binding molecules is not however completely understood. CD11b/CD18 and CD11c/CD18 are also known as MAC-1 and p150, 95 respectively. They are members of the &bgr;
2
integrin family (sometimes known as Leu-CAM, ie leucocyte cell adhesion molecules). This family also includes LFA-1 amongst its members (also known as CD11a/CD18).
EP 0205405 purports to disclose Mabs to lymphocyte cellular receptors for IgE (FC&egr;R) cross reacting with human immunoglobulin E binding factor (IgE-BF), and derivatives thereof.
WO 93/04173 purports to disclose a polypeptide which is capable of binding to one of FCEL (low affinity IgE receptor FC&egr;RII) or FCEH (high affinity receptor FC&egr;RI) but which is substantially incapable of binding to the other of FCEL or FCEH. Treatment of an allergic disorder is alleged with a FCEL or FCEH specific polypeptide (provided the FCEH specific polypeptide is incapable of crosslinking FCEH and inducing histamine release).
EP 0269728 purports to disclose Mabs to the human lymphocyte IgE receptor.
EP 0259585 purports to disclose Mabs recognising a surface receptor for IgE (FC&egr;R) on human B lymphocytes.
WO 93/02108 purports to disclose primatised antibodies for therapeutic use.
The present inventors have surprisingly discovered that binding agents to CD23 can be of utility in the treatment or prophylaxis of various diseases and in particular in the treatment or prophylaxis of arthritis. Prior to the present invention no data has been presented which would support such a utility, despite the publication of a large number of papers in which CD23 has been discussed.
According to the present invention, there is provided a binding agent to CD23 for use in the treatment or prophylaxis of inflammatory, autoimmune or allergic diseases.
The binding agent may function by blocking the interaction between CD23 and a ligand which binds to it. In vitro assays e.g. radioimmune assays may be used to study such a blocking effect
The binding agent may be in isolated form or as part of a pharmaceutical composition. Desirably it is in sterile form. Generally speaking a binding agent which is specific for CD23 is useful in the treatment/prophylaxis disclosed.
The present inventors have demonstrated that binding agents within the scope of the present invention work in vivo in treatment or prophylaxis of inflammatory or autoimmune diseases.
This demonstration is of great significance, given the fact that many of these diseases are difficult or impossible to treat effectively, despite long standing research into their nature and causes. This is particularly the case in respect of arthritis, which often affects people in middle age and can cause them to give up work prematurely. An effective treatment of arthritis has been a long standing goal of many research groups.
Preferred binding agents include antibodies, fragments thereof or artificial constructs comprising antibodies or fragments thereof or artificial constructs designed to mimic the binding of antibodies or fragments thereof. Such binding agents are discussed by Dougall et al in
Tibtech
12, 372-379 (1994).
They include complete antibodies, F(ab′)
2
fragments, Fab fragments, Fv fragments, SCFv fragments, other fragments, CDR peptides and mimetics. These can be obtained/prepared by those skilled in the art. For example, enzyme digestion can be used to obtain F(ab′)
2
and Fab fragments (by subjecting an IgG to molecule to pepsin or papain cleavage respectively). References to “antibodies” in the following description should be taken to include all of the possibilities mentioned above.
Recombinant antibodies may be used. The antibodies may be humanized; or chimaerised.
A typical preparation of a humanised antibody in which the CDRs are derived from a different species than the framework of the antibody's variable domains is disclosed in EP-A-0239400. The CDRs may be derived from a rat or mouse monoclonal antibody. The framework of the variable domains, and the constant domains, of the altered antibody may be derived from a human antibody. Such a humanised antibody elicits a negligible immune response when administered to a human compared to the immune response mounted by a human against a rat or mouse antibody.
Alternatively, the antibody may be a chimaeric antibody, for instance of the type described in WO 86/01533.
A chimaeric antibody according to WO 86/01533 comprises an antigen binding region and a non-immunoglobulin region. The antigen binding region is an antibody light chain variable domain or heavy chain variable domain. Typically, the chimaeric antibody comprises both light and heavy chain variable domains. The non-immunoglobulin region is fused at its C-terminus to the antigen binding region. The non-immunoglobulin region is typically a non-immunoglobulin protein and may be an enzyme region, a region derived from a protein having known binding specificity, from a protein toxin or indeed from any protein expressed by a gene. The t
Nixon & Vanderhye P.C.
Saunders David
Smithkline Beecham Corporation
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